The aim of this project is to define the molecular mechanisms and biological contexts for blood leukocyte migration to specific tissue sites that are inflamed or infected. We have focused on chemoattractant proteins that mediate this process and have identified members of a large family of chemoattractant receptors that are deployed on the leukocyte cell surface. We have also identified members of a diverse group of chemoattractant and chemoattractant receptor mimics made by viruses, including herpesviruses, poxviruses and HIV. We use genomics, molecular biology, cell biology and epidemiology as the principle methods for analyzing these molecules. A major goal is to identify specific disease associations of individual chemoattractant and chemoattractant receptors, in order to identify potential new therapeutic targets. A key strategy is to analyze phenotypes of gene knockout mice in disease models as well as associations of loss of function mutations in the corresponding human genes in human disease cohorts. In FY07 we continued our study of chemokine regulation of atherosclerosis. Extending our previous report in FY06 that pathogenic atherosclerosis-associated oxidized lipids are able to reciprocally regulate expression of the chemokine receptors CCR2 (decreased) and CX3CR1 (increased) on primary human macrophages developed from blood monocytes ex vivo, in FY07 we focused on the CX3CR1 ligand CX3CL1 and found that its expression was also upregulated by these pathogenic lipids, on both macrophages and primary human coronary artery smooth muscle cells (CASMCs). The CX3CL1-CX3CR1 ligand-receptor pair is a major mediator of static adhesion of macrophages to CASMCs in this sytem. Together the results suggest a model for foam cell recruitment and retention within plaque in which CX3CL1-CX3CR1 act to coordinate adhesion of macrophages to CASMCs in the vessel wall through both homotypic and heterotypic adhesive interactions. This provides a novel model of atherogenesis and identifies CX3CL1-CX3CR1 as a potential new drug target in this disease. Moreover, the data provide an explanation at the molecular and cellular level for genetic and epidemiologic data we reported earlier showing that CX3CR1 is a proatherogenic factor. In FY07 we also defined a signal transduction pathway involved in CX3CL1 upregulation by oxidized lipids involving an autocrine/paracrine TNF-dependent pathway and the transcription factor NF-kB. Interestingly, upregulation of CX3CR1 on macrophages by the same lipids occurs through a different mechanism involving the transcription factor PPAR-gamma. In FY07 we also defined F2L, a breakdown production of hemoglobin found at sights of inflammation, as a functional ligand for the formylpeptide receptor homologue FPR2. One of the first endogenous ligands found for this receptor, this new finding provides an important new direction for analyzing the biological role of FPR2.